IMPACT Progress

Biology Strand
1. Biocompatibility testing
One of the important considerations for the use of medical devices designed for implantation within the human body is their functionality following implantation. Unfortunately, following implantation medical devices may lose their ability to function correctly due to the immune response that occurs, this reaction is caused by the foreign body response (FBR), the extent of this response is affected by the biocompatability of the device. We have now assessed the biocompatibility of the IMPACT sensor materials (silicon dioxide, silicon nitride, Parylene-C, Nafion, biocompatable EPOTEK epoxy resin and platinum) within a tumour. We have successfully shown that the materials had no effect on tumour necrosis, hypoxic cell number, proliferation, apoptosis, immune cell infiltration or collagen deposition. The absence of a significant FBR supports the use of these materials in or IMPACT sensors.
2. Validation of sensor functionality
Pre-clinical in vivo testing of functional oxygen and pH sensors was carried out following biocompatibility testing. We developed 2 novel animal models (rat and sheep) for the validation of our IMPACT sensors through which we have shown a variety of potential clinical applications for our sensors. Using our rat model, we were able to detect changes in intestinal oxygenation using the IMPACT oxygen sensor. We envisage that these sensors could be used in patients that have undergone partial bowel resection for real-time post-operative monitoring of oxygenation at the join of the remaining bowel segments. Monitoring intestinal oxygenation (a surrogate of blood supply) would allow the identification of patients at risk of breakdown of the joined intestinal sections, this could allow for earlier surgical intervention to repair the join. Using our sheep model, we have successfully measured intra-tumoural oxygenation and pH within naturally occurring lung tumours. Our results have shown that our using our implantation technique we are able to deliver our sensors within a tumour and make real-time measurements. We have also shown that the sensors can function when exposed to therapeutic doses of radiation providing excellent evidence to build upon in future trials progressing onto clinical studies in man.  
3. Identification of cellular markers of radiation response and resistance
For the development of an implantable sensor that could measure a tumour’s response to radiotherapy we needed to identify proteins/biomarkers that could be detected by our IMPACT sensors. These biomarkers would be cellular proteins that are released by radiosensitive tumour cells, but not radioresistant ones, upon treatment with a dose of radiation (radiotherapy). To identify these biomarkers, we first developed radioresistant cancer cell lines. We analysed differences in the response to radiation between these radioresistant and radiosensitive cell lines and have successfully identified a panel of 9 candidate biomarkers released by radiosensitive tumour cells. These have the potential to be taken forward to be incorporated into a next generation IMPACT sensor to be used as an implantable radiotherapy monitoring device. We will need to identify whether these biomarkers of radiosensitivity are cancer type specific or represent markers released from a variety of tumours. 
1) Review -M.Gray, J.Meehan, C.Ward, S.P.Langdon, I.H.Kunkler, A.Murray, D.Argyle. Implantable biosensors and their contribution to the future of precision medicine. The veterinary journal 2018; 239; 21-29. 
2) Original article – M.Gray, J.Meehan, E.O.Blair, C.Ward, S.P.Langdon, L.R.Morrison, J.R.K.Marland, A.Tsiamis, I.H.Kunkler, A.Murray, D.Argyle. Biocompatibility of Common Implantable Sensor Materials in a Tumour Xenograft Model. Biomaterials and Research Part B 2018.
3) Review - C.Ward, J.Meehan, M.Gray, I.H.Kunkler, S.P.Langdon, D.Argyle. Carbonic Anhydrase IX (CAIX), Cancer, and Radiation Responsiveness. Metabolites 2018; 8(1); 1-9.
4) Book chapter – C.Ward, J.Meehan, M.Gray, I.H.Kunkler, S.P.Langdon, A.Murray, D.Argyle. Preclinical Organotypic Models for the Assessment of Novel Cancer Therapeutics and Treatment.
1) Original article - Development and Characterisation of Acquired Radioresistant Breast Cancer Cell Lines. Breast cancer research.
In Writing:
1) Original article - Tumour-secreted predictive biomarkers of response to radiotherapy in breast and other cancers
2) Validation of a Miniaturised Clark Oxygen Sensor to Measure Intestinal Oxygenation Tensions for Clinical Applications